Blood vessels were once thought to be an infrastructure of the body that had no significantly active function, and their biology was of little concern for biomedical investigators and physicians. However, recent progress in vascular biology has revealed that blood vessels, especially endothelial cells are metabolically highly active and perform multifaceted functions, such as synthesizing a host of physiologically active substances, receiving and transmitting signals, and controlling the passage of molecules and cells across the vessel wall. Thus, maintaining healthy endothelium should be a matter of high priority in nation's health program. There are known risk factors (such as high levels of lipids in blood, hypertension, stress, smoking, male hormone, age and genetic make-up of an individual) for atherosclerosis, and, most of them are systemic factors. However, the initial occurrence of atherosclerotic legions is limited to specific regions within the artery, suggesting that in addition to these systemic factors, some important local factor(s) must exist. The areas within the artery where atherogenesis occurs are the regions of disturbed laminar flow or decreased fluid shear stress. Many studies have shown that endothelial cell physiology is very sensitive to fluid shear stress, frictional force of flowing blood that acts on the endothelial cell surface. The project proposes to study the molecular mechanism of flow sensing by endothelial cells. The study should provide new information and insights regarding two important questions in endothelial and vascular cell biology: 1) the molecular mechanism of FSS sensing and 2) the subsequent signal transduction events. At the clinical level, our study should provide a set of new points of pharmacological and other means of intervention in order to prevent and control the development of vascular diseases, in particular atherogenesis